The proposed research is aimed at characterizing the safety and efficacy profiles to address FDA-defined gaps in the clinical development program for lofexidine hydrochloride, an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short-acting opioids. The program includes two linked studies to be conducted consecutively at the same sites: Study 1 will generate pivotal efficacy/safety data for two doses of lofexidine hydrochloride in 600 subjects about to undergo total and abrupt withdrawal from short- acting opioids who will be randomized under double-blind conditions to either placebo (N=150) or lofexidine (2.4 mg or 3.2 mg total daily dose; N=225/group) for 7 days of inpatient treatment. Subsequently, all subjects will be permitted to continue under open-label conditions for up to an additional 7 days of inpatient/outpatient, variable-dose treatment depending on the wishes of the Site Investigator and subject. Safety will be assessed by evaluation of adverse event (AE), clinical laboratory, electrocardiogram (with special attention to QTc), vital signs, and physical exam data. Efficacy will be evaluated daily by subject- and observer-completed scales including the Short Opiate Withdrawal Scale of Gossop (SOWS-G) (the primary outcome measure is SOWS-G score area under the curve for Days 1-7), the Objective Opiate Withdrawal Scale (OOWS-Handelsman), the Visual Analog Scale for Efficacy (VAS-E), and the Modified Clinical Global Impressions scales for efficacy and side effects. Efficacy will also be evaluated by study retention, completion rates, concomitant medication use, incidence of withdrawal-related AEs, and subject treatment status 30 days post discharge. Study 2 will follow a similar 14-day dosing format but will be entirely open-label; and 200 to 400 subjects (different from those in Study 1) will receive lofexidine at a variable dose not to exceed a total of 3.2 mg per day or a single dose of 0.8 mg in an inpatient, outpatient, or a combination of settings as per the normal standard of care at the enrolling site. Study 2 is a translational research design aimed at gathering real-world effectiveness and safety data to supplement the existing lofexidine safety database and enable appropriate product labeling for end-users. Safety will be evaluated for all treated subjects and for two cohorts: those with urines negative and those with urines positive for drugs of abuse so that all possible causes of reported AEs may be considered for analysis. Effectiveness will be evaluated by the Clinical Opiate Withdrawal Scale (COWS), rate of detoxification completion, and subject treatment status 30 days post discharge. An open-label, variable-dose, real-world design as planned in Study 2 is common in Phase 3 drug development, and together with Study 1, which will provide pivotal efficacy data needed to support the proposed product indication, the program has been designed to address FDA registration requirements for lofexidine. On approval of an NDA, lofexidine will be the first approved non-narcotic, non-addictive drug indicated for treatment of opioid withdrawal in the US, providing an important alternative therapy for this indication.